The human granulocytic ehrlichiosis (HGE) agent is a newly identified zoonotic pathogen capable of causing a potentially fatal illness. In the USA, it is transmitted by Ixodes ticks in areas that essentially overlap the distribution of Lyme disease owing to the fact that both agents share the same vector. Serologic surveys indicate that the disease is widespread also in Europe where it has recently been identified in a human patient. Last year, two research groups isolated the etiologic agent from human patients (Goodman et al. 1996) and a horse (Munderloh et al. 1996), utilizing cell culture systems that represent the spectrum of the life cycle of the agent in nature, a human promyelocytic leukemia cell line and an Ixodes scapularis tick cell line, respectively. These achievements have opened the way to investigate the cellular and molecular biology of the agent in vitro in human and vector cell systems. The development of the agent in tick cell culture differs strikingly from its growth in human cells, hinting at specific adaptations to these divergent hosts. In collaboration with Dr. Goodman, I have identified hamsters as a small laboratory animal that is susceptible to the agent from human and tick cell culture, and I. scapularis ticks have experimentally transmitted it to hamsters. Hamsters developed infections of bone-marrow cells and developed hematologic signs similar to those seen in humans. This proposal aims 1) to elucidate in detail the interaction of the HGE agent with its vector in vivo and in vitro, focussing on environmental cues that stimulate development and expression of surface proteins which could serve as ligands during invasion. These changes will be related to infectivity and pathogenicity for cultured cells and mammalian hosts; 2) to determine the role of transstadial vs transovarial maintenance in the natural history of the HGE agent; 3) to characterize the antigenic profile of the agent in tick cell culture and in ticks which are presumably representative of the make-up of immunogens first encountered by the mammal, and which may have implications for diagnosis and vaccine development.